Patel Kashyap A, Kettunen Jarno, Laakso Markku, Stančáková Alena, Laver Thomas W, Colclough Kevin, Johnson Matthew B, Abramowicz Marc, Groop Leif, Miettinen Päivi J, Shepherd Maggie H, Flanagan Sarah E, Ellard Sian, Inagaki Nobuya, Hattersley Andrew T, Tuomi Tiinamaija, Cnop Miriam, Weedon Michael N
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK.
Department of Endocrinology, Abdominal Centre, Helsinki University Hospital, Helsinki, 00029, Finland.
Nat Commun. 2017 Oct 12;8(1):888. doi: 10.1038/s41467-017-00895-9.
Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10) and Finnish (n = 80, odds ratio = 22, P = 1 × 10) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.
寻找单基因糖尿病的新病因有助于了解人类的血糖调节。为了找到青年发病的成年型糖尿病（MODY）的新遗传病因，我们对病因不明的MODY病例进行了测序，并将变异频率与大型公共数据库进行了比较。在36名欧洲患者中，我们鉴定出两名携带新型RFX6杂合无义变异的先证者。与ExAC中的欧洲对照人群相比，RFX6蛋白截短变异在MODY发现队列中更为富集（优势比=131，P=1×10）。我们在非芬兰欧洲人（n=348，优势比=43，P=5×10）和芬兰人（n=80，优势比=22，P=1×10）的复制队列中也发现了类似结果。与常见的HNF1A和HNF4A-MODY突变相比，RFX6杂合子的糖尿病外显率降低（25岁时分别为27%、70%和55%）。高血糖是由β细胞功能障碍引起的，并且与较低的空腹和刺激后的胃抑制多肽（GIP）水平相关。我们的研究表明，杂合的RFX6蛋白截短变异与外显率降低的MODY相关。青年发病的成年型糖尿病（MODY）是家族性糖尿病最常见的亚型。在这里，帕特尔等人利用MODY患者的靶向DNA测序和大规模公开可用数据表明，RFX6杂合蛋白截短变异导致外显率降低的MODY。
